Benzenesulfonamide derivatives as antipsychotic agents

ABSTRACT

The invention provides compounds of formula (I)  
                 
wherein 
         A and B represent the groups —(CH 2 ) m - and —(CH 2 ) n -respectively;    R 1  represents hydrogen or C 1-6 alkyl;    R 2  represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC 1-6 alkyl, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkoxy, —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) p C 3-6 cycloalkyloxy, —COC 1-6 alkyl, —SO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —S—C 1-6 alkyl, C 1-6 alkylsulfonyloxy, C 1-6 alkylsulfonylC 1-6 alkyl, —CO 2 C 1-6 alkyl, —CO 2 NR 7 R 8 , —SO 2 NR 7 R 8 , C 1-6 alkylsulfonamido, C 1-6 alkylsulfonamidoC 1-6 alkyl, —(CH 2 ) p NR 7 R 8 , C 1-6 alkylamidoC 1-6 alkyl, —(CH 2 ) p NR 7 COR 8 , arylsulfonyl, arylsulfonyloxy, arylsulfonylC 1-6 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC 1-6 alkyl, arylcarboxamidoC 1-6 alkyl, aroyl, aroylC 1-6 alkyl, arylC 1-6 alkanoyl, —SO 2 NR 7 R 8 , optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl, or a group CONR 7 R 8  or SO 2 NR 7 R 8  wherein R 7  and R 8  together may be fused to form a 5- 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom;    R 3  represents hydrogen or C 1-6 alkyl; Ar represents optionally substituted phenyl or optionally substituted monocyclic heteroaryl group;    R 4  represents optionally substituted aryl or optionally substituted heteroaryl;    R 7  and R 8  each independently represent hydrogen, C 1-6 alkyl or together form a 5- to 7-membered heterocyclic ring;    Z represents a bond, an oxygen atom or C 1-6 alkyl;    Y represents hydrogen or C 1-6 alkyl; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; q represents an integer from 1 to 3; r represents an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof. The compounds are useful in therapy, in particular as antipsychotic agents.

This invention relates to novel compounds, pharmaceutical compositionscontaining them and their use in therapy, in particular as antipsychoticagents.

WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WO 01/32646(SmithKline Beecham plc) disclose a series of aryl sulfonamide andsulfoxide compounds that are said to be 5-HT₆ receptor antagonists andwhich are claimed to be useful in the treatment of various CNSdisorders.

WO 01/62737 discloses amino pyrazole derivatives useful for thetreatment of obesity and other disorders associated with the NPYreceptor subtype Y5.

EP0937723 discloses sulfonamide compounds useful in the treatment ofthrombolytic disorders.

WO 01/85695 discloses tetrahydroisoquinoline analogues useful as growthhormone secretagogues.

U.S. Pat. No. 5,684,195 discloses a method of preparing sulfonamidesfrom sulfones.

WO 02/46164 discloses aryl sulfonamide compounds that are said to beuseful as selective ER-β ligands in the treatment or prophylaxis ofAlzheimer's disease, anxiety disorders, depressive disorders,osteoporosis, cardiovascular disease, rheumatoid arthritis or prostatecancer.

A structurally novel class of compounds has now been found which areuseful as antipsychotic agents and for the treatment of other disorders.

According to the invention, there is provided a compound of formula (I):

wherein

A and B represent the groups —(CH₂)_(m)- and —(CH₂)_(n)-respectively;

R¹ represents hydrogen or C₁₋₆alkyl;

R² represents hydrogen, halogen, hydroxy, cyano, nitro,hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy,—(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(p)C₃₋₆cycloalkyloxy, —COC₁₋₆alkyl,—SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, C₁₋₆alkylsulfonyloxy,C₁₋₆alkylsulfonylC₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸, —SO₂NR⁷R⁸,C₁₋₆alkylsulfonamido, C₁₋₆alkylsulfonamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷R⁸,C₁₋₆alkylamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷COR⁸, arylsulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆alkyl, arylsulfonamido,arylcarboxamido, arylsulfonamidoC₁₋₆alkyl, arylcarboxamidoC₁₋₆alkyl,aroyl, aroylC₁₋₆alkyl, arylC₁₋₆alkanoyl, —SO₂NR⁷R⁸, optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl, or a group CONR⁷R⁸ or SO₂NR⁷R⁸ wherein R⁷ andR⁸ together may be fused to form a 5- 7-membered aromatic ornon-aromatic heterocyclic ring optionally interrupted by an O or S atom;

R³ represents hydrogen or C₁₋₆alkyl;

Ar represents optionally substituted phenyl or optionally substitutedmonocyclic heteroaryl group;

R⁴ represents optionally substituted aryl or optionally substitutedheteroaryl;

R⁷ and R⁸ each independently represent hydrogen, C₁₋₆alkyl or togetherform a 5- to 7-membered heterocyclic ring;

Z represents a bond, an oxygen atom or C₁₋₆alkylene;

Y represents hydrogen or C₁₋₆alkyl;

m and n independently represent an integer selected from 1 and 2;

p independently represents an integer selected from 0, 1, 2 and 3;

q represents an integer from 1 to 3;

r represents an integer from 1 to 4;

or a pharmaceutically acceptable salt or solvate thereof.

As a further aspect of the invention, there is provided a compound offormula (I) wherein A, B, Y, Z, q, r, Ar and R¹ to R⁴ have any of themeanings as hereinbefore described, with the proviso that when R¹represents C₁₋₆alkyl and Y represents hydrogen, Ar cannot represent anoptionally substituted monocyclic heteroaryl group.

As used herein, the term “alkyl”, either alone or as part of anothergroup, refers to straight or branched hydrocarbon chains containing thespecified number of carbon atoms. For example, C₁₋₆alkyl means astraight or branched alkyl containing at least 1, and at most 6, carbonatoms. Examples of “alkyl” as used herein include, but are not limitedto, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl,isopropyl, t-butyl and 1,1-dimethylpropyl.

As used herein, the term “alkoxy” refers to a straight or branchedalkoxy group containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy group containingat least 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy or hexyloxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms. Forexample, C₃₋₇cycloalkyl means a non-aromatic ring containing at leastthree, and at most seven, ring carbon atoms. Examples of “cycloalkyl” asused herein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₆₋₇cycloalkyl group ispreferred.

As used herein, the term “halogen” refers to the elements fluorine,chlorine, bromine and iodine. Preferred halogens are fluorine, chlorineand bromine.

As used herein, the term “aryl” refers to a phenyl or a naphthyl ring.

As used herein, the term “heteroaryl” refers to a 5- or 6-memberedheterocyclic aromatic ring or a fused bicyclic heterocyclic ring system.

As used herein, the term “heterocyclyl” refers to a 3- to 7-memberedmonocyclic saturated ring containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Examples ofsuitable heterocyclic rings include, but are not limited to, piperidineand morpholine.

As used herein, the term “5- or 6-membered heterocyclic aromatic ring”refers to a monocyclic unsaturated ring containing at least oneheteroatom independently selected from oxygen, nitrogen and sulfur.Examples of suitable 5- and 6-membered heterocyclic aromatic ringsinclude, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl,triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl andisoxazolyl.

As used herein, the term “fused bicyclic heterocyclic ring system”refers to a ring system comprising two 5- to 7-membered saturated orunsaturated rings, the ring system containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Preferably,each ring has 5 or 6 ring atoms. Examples of suitable fused bicyclicrings include, but are not limited to, indolyl, indolinyl, benzofuranyl,benzothienyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzodioxanyl,indanyl and tetrahydronapthyl.

As used herein, the term “optionally substituted” refers to optionalsubstitution with the named substituent or substituents, multipledegrees of substitution being allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Most preferably the solvent used is water andthe solvate may also be referred to as a hydrate.

It will be appreciated that for use in medicine the salts of formula (I)should be pharmaceutically acceptable. Suitable pharmaceuticallyacceptable salts will be apparent to those skilled in the art andinclude for example acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Other non-pharmaceutically acceptable salts e.g. oxalates, may be used,for example in the isolation of compounds of formula (I) and areincluded within the scope of this invention. Also included within thescope of the invention are solvates and hydrates of the compounds offormula (I).

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms thereof.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The presentinvention also covers the individual isomers of the compoundsrepresented by formula (I) as mixtures with isomers thereof in which oneor more chiral centres are inverted. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

The groups R², R⁵ and R⁶ may be located on any free position on theirrespective phenyl rings. The Y group(s) may be located on any freeposition on the respective ring.

When R², R⁴, R⁵ or R⁶ represent optionally substituted aryl oroptionally substituted heteroaryl or R² additionally representsoptionally substituted heterocyclyl, the optional substituents may beindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen,trifluoromethyl, trifluoromethoxy, cyano, nitro, —NR⁷R⁸, —C₁₋₆alkylS and—S—C₁₋₆alkyl. More preferably, the optional substituents for the groupsR², R⁴, R⁵ and R⁶ are independently selected from chloro, fluoro, bromo,methyl, ethyl, t-butyl, methoxy, trifluoromethyl, trifluoromethoxy,cyano, nitro, —S-methyl, methyl-S and —NR⁷R⁸.

When Ar represents optionally substituted phenyl or optionallysubstituted monocyclic heteroaryl, the optional susbtituents areindependently selected from hydrogen, halogen, hydroxy, cyano, nitro,hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloallylC₁₋₆alkoxy,—(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(p)C₃₋₆cycloalkyloxy, —COC₁₋₆alkyl,—SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —C₁₋₆alkylS,C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆alkyl, —CO₂C₁₋₆alkyl,—CO₂NR⁷R⁸, —SO₂NR⁷R⁸, C₁₋₆alkylsulfonamido,C₁₋₆alkylsulfonamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷R⁸, C₁₋₆alkylamidoC₁₋₆alkyl,—(CH₂)_(p)NR⁷COR⁸, aryl sulfonyl, arylsulfonyloxy,arylsulfonylC₁₋₆alkyl, arylsulfonamido, arylcarboxamido,arylsulfonamidoC₁₋₆alkyl, arylcarboxamidoC₁₋₆alkyl, aroyl,aroylC₁₋₆alkyl, arylC₁₋₆alkanoyl, —SO₂NR⁷R⁸, optionally substituted arylor optionally substituted heteroaryl, or a group CONR⁷R⁸ or SO₂NR⁷R⁸wherein R⁷ and R⁸ together may be fused to form a 5- to 7-memberedaromatic or non-aromatic heterocyclic ring optionally interrupted by anO or S atom.

Preferably, R¹ represents hydrogen or C₁₋₄alkyl. More preferably, R¹represents hydrogen, methyl, ethyl, n-propyl, isopropyl, t-butyl orn-butyl. Even more preferably, R¹ represents hydrogen, methyl, ethyl,n-propyl or isopropyl. Even more preferably, R¹ represents hydrogen ormethyl.

Preferably, R² represents hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,—C₁₋₆alkylS, —S—C₁₋₆alkyl, —NR⁷R⁸ or optionally substitutedheterocyclyl. In particular, R² represents methyl, ethyl, methoxy,ethoxy, isopropoxy, bromo, chloro, dimethylamino, —S-ethyl, -ethyl-S orpiperidyl. More preferably, R² represents hydrogen, halogen, C₁₋₆alkylor C₁₋₆alkoxy. Even more preferably, R² represents hydrogen, halogen,C₁₋₄alkyl or C₁₋₄alkoxy. Even more preferably, R² represents hydrogen,dimethylamino, methoxy, ethoxy or isopropoxy.

Preferably, R³ represents hydrogen or C₁₋₄alkyl. More preferably, R³represents hydrogen, methyl, ethyl, n-propyl or isopropyl. Even morepreferably, R³ represents hydrogen, methyl or isopropyl.

Preferably, R⁴ represents phenyl, naphthyl, thienyl, benzofuranyl,furyl, benzothienyl, pyridyl, isoxazolyl and pyrrolyl, all of which maybe optionally substituted. More preferably, R⁴ represents phenyl,naphthyl, thienyl, benzofuranyl, furyl or benzothienyl, all of which maybe optionally substituted. Even more preferably, R⁴ represents phenyl orthienyl (e.g. 2-thienyl or 3-thienyl).

If R⁴ is optionally substituted, preferably R⁴ is mono- ordi-substituted. In particular, when R⁴ is phenyl, the optionalsubstituents may be independently selected from chloro (e.g. 2-, 3- or4-chloro), bromo (e.g. 4-bromo), fluoro (e.g. 2-, 3- or 4-fluoro),dichloro (e.g. 2,4- or 3,4-dichloro), difluoro (e.g. 2,4-, 3,4- or3,5-difluoro), trifluoromethyl (e.g. 4-trifluoromethyl), methyl (e.g.2-, 3- or 4-methyl), t-butyl (e.g. 4-t-butyl), methoxy (e.g. 4-methoxy),trifluoromethoxy (e.g. 4-trifluoromethoxy), cyano (e.g. 4-cyano), nitro(e.g. 4-nitro), dimethylamino (e.g. 4-dimethylamino), -methyl-S (e.g.4-methyl-S), or methyl and chloro together (e.g. 2-methyl-4-chloro or3-methyl-4-chloro). More preferably, when R⁴ is phenyl, one of theoptional substituents is located at the 4-position relative to theattachment of R⁴ to the rest of the molecule.

When R⁴ is thienyl, the optional substituents may be independentlyselected from chloro (e.g. 5-chloro) or methyl (e.g. 4- or 5-methyl).

Preferably, R⁷ and R⁸ independently represent hydrogen or C₁₋₄alkyl.More preferably, R⁷ and R⁸ independently represent hydrogen or methyl.

Preferably, Ar represents optionally substituted phenyl.

Preferably, Z represents a bond or oxygen. More preferably, Z representsa bond.

Preferably, Y represents hydrogen.

Preferably, p represents 0.

Preferably, q represents 1.

Preferably, r represents 1.

According to a further aspect of the invention, there is provided acompound of formula (I) wherein Ar represents a phenyl ring, i.e. acompound of formula (IA):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups A, B, R¹ to R⁴, Z, Y, q and r have any of the meanings as givenhereinbefore and R⁵ and R⁶ each independently represent hydrogen,halogen, hydroxy, cyano, nitro, hydroxyC₁₋₆alkyl, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆alkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl,—(CH₂)_(p)C₃₋₆cycloalkyloxy, —COC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl,—S—C₁₋₆alkyl, —C₁₋₆alkylS, C₁₋₆alkylsulfonyloxy,C₁₋₆alkylsulfonylC₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸, —SO₂NR⁷R⁸,C₁₋₆alkylsulfonamido, C₁₋₆alkylsulfonamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷R⁸,C₁₋₆alkylamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷COR⁸, aryl sulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆alkyl, arylsulfonamido,arylcarboxamido, arylsulfonamidoC₁₋₆alkyl, arylcarboxamidoC₁₋₆alkyl,aroyl, aroylC₁₋₆alkyl, arylC₁₋₆alkanoyl, —SO₂NR⁷R⁸, optionallysubstituted aryl or optionally substituted heteroaryl, or a groupCONR⁷R⁸ or SO₂NR⁷R⁸ wherein R⁷ and R⁸ together may be fused to form a 5-to 7-membered aromatic or non-aromatic heterocyclic ring optionallyinterrupted by an O or S atom.

Preferably, R⁵ and R⁶ independently represent hydrogen, methyl, fluoroor chloro.

According to a further aspect of the invention, there is provided acompound of formula (IA) wherein q represents 1, r represents 1 and Yrepresents hydrogen, i.e. a compound of the formula (IB):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups A, B, R¹ to R⁶ and Z have any of the meanings as givenhereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (IB) wherein the R² group is located at thepara-position relative to the group B, i.e. a compound of formula (IC):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups A, B, R¹ to R⁶ and Z have any of the meanings as givenhereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (IB) wherein the group -Z-R⁴ is located at thepara-position relative to the sulfonamide group, i.e. a compound offormula (ID))

wherein

A and B represent the groups —(CH₂)_(m)- and —(CH₂)_(n)-respectively;

R¹ represents hydrogen or C₁₋₆alkyl;

R² represents hydrogen, halogen, hydroxy, cyano, nitro,hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(p)C₃₋₆cycloalkyloxy,—COC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl,—CO₂NR⁷R⁸, —SO₂NR⁷R⁸, —(CH₂)_(p)NR⁷R⁸, —(CH₂)_(p)NR⁷COR⁸, optionallysubstituted aryl, optionally substituted heteroaryl, a fused bicyclicheterocyclic ring system or optionally substituted heterocyclyl;

R³ represents hydrogen or C₁₋₆alkyl;

R⁴ represents optionally substituted aryl or optionally substitutedheteroaryl;

R⁵ and R⁶ each independently represent hydrogen, halogen, hydroxy,cyano, nitro, hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy,C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl,—(CH₂)_(p)C₃₋₆cycloalkyloxy, —COC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl,—S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸, —SO₂NR⁷R⁸, —(CH₂)_(p)NR⁷R⁸,—(CH₂)_(p)NR⁷COR⁸, optionally substituted aryl, optionally substitutedheteroaryl or a fused bicyclic heterocyclic ring system;

R⁷ and R⁸ each independently represent hydrogen or C₁₋₆alkyl;

Z represents a bond, an oxygen atom or C₁₋₆alkylene;

m and n independently represent an integer selected from 1 and 2;

p independently represents an integer selected from 0, 1, 2 and 3;

or a pharmaceutically acceptable salt or solvate thereof.

According to a further aspect of the invention, there is provided acompound of formula (ID) wherein m is 1 and n is 1, i.e. a compound offormula (IE):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (ID) wherein m is 2 and n is 1, i.e. a compound offormula (IF):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (ID) wherein m is 1 and n is 2, i.e. a compound offormula (IG):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (IB) wherein m is 2 and n is 2, i.e. a compound offormula (IH):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (ID) wherein m is 2 and n is 2, i.e. a compound offormula (IJ):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (IJ) wherein the R² group is located at thepara-position relative to the group B, i.e. a compound of formula (IK):

or a pharmaceutically acceptable salt or solvate thereof wherein thegroups Z and R¹ to R⁶ have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided acompound of formula (I) wherein R¹ and R³ both represent hydrogen, m andn both represent 2 and Z represents a bond, i.e. a compound of formula(IL):

wherein:

R² represents hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, trifluoromethanesulfonyloxy,pentafluoroethyl, C₁₋₆alkoxy, arylC₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl,C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆alkyl, arylsulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆alkyl, C₁₋₆alkylsulfonamido,C₁₋₆alkylamido, C₁₋₆alkylsulfonamidoC₁₋₆alkyl, C₁₋₆alkylamidoC₁₋₆alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamidoC₁₋₆alkyl,arylcarboxamidoC₁₋₆alkyl, aroyl, aroylC₁₋₆alkyl, arylC₁₋₆alkanoyl, or agroup CONR⁷R⁸ or SO₂NR⁷R⁸, wherein R⁷ and R⁸ independently representhydrogen or C₁₋₆alkyl or together may be fused to form a 5- to7-membered aromatic or non-aromatic heterocyclic ring optionallyinterrupted by an O or S atom;

Y represents hydrogen or C₁₋₆alkyl;

q represents an integer from 1 to 3;

r represents an integer from 1 to 4;

Ar and R⁴ independently represent phenyl or a monocyclic heteroarylgroup each of which may be optionally substituted;

Ar and R⁴ may be optionally substituted by one or more substituentswhich may be the same or different, and which are selected from thosedefined for R²;

or solvates thereof.

According to a further aspect of the invention, there is provided acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof wherein the groups A, B, R¹ to R⁴, Y, q and r have any of themeanings as given hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IA) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups A, B, R¹ to R⁴, Y, q and r have anyof the meanings as given hereinbefore and Z represents oxygen orC₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IB) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups A, B and R¹ to R⁶ have any of themeanings as given hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IC) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups A, B and R¹ to R⁶ have any of themeanings as given hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (ID) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups A, B and R¹ to R⁶ have any of themeanings as given hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IE) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IF) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IG) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IH) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IJ) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IK) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

According to a further aspect of the invention, there is provided acompound of formula (IL) or a pharmaceutically acceptable salt orsolvate thereof wherein the groups R¹ to R⁶ have any of the meanings asgiven hereinbefore and Z represents oxygen or C₁₋₆alkylene.

In a preferred aspect of the invention, compounds of formula (I) are ofthe formulae (IE), (IF), (IH), (IJ) and (IK) or a pharmaceuticallyacceptable salt or solvate thereof wherein the groups Z and R¹ to R⁶have any of the meanings as given hereinbefore.

Particular compounds according to the invention include thoseincorporated in Tables 1 to 3 and those specifically exemplified andnamed hereinafter including, without limitation:

4-(4-Chloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-N-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-N-(2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-3-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-3-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;

4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;

4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide;

4-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide;

4-(4-Chloro-phenyl)-N-(8-dimethylamino-3-methyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-benzenesulfonamidehydrochloride and

4-(4-fluorobenzyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamidehydrochloride.

The compounds of the present invention may be in the form of their freebase or pharmaceutically acceptable salts thereof, particularly themonohydrochloride salt.

The present invention also provides a general process (A) for preparingcompounds of formula (I) which process comprises:

reacting a compound of formula (II)

with a compound of formula (III)

wherein A, B, Z, q and r are as hereinbefore defined and R^(1′)-R^(4′)and Y′ represent R¹ to R⁴ and Y as hereinbefore defined or are groupsthat may be readily convertible to R¹ to R⁴.

This general method (A) can be conveniently performed by mixing the twocomponents in a suitable solvent such as pyridine or dichloromethane (inthe presence of a base), at 0° C.

According to a further aspect of the invention, when compounds of theformula (ID) are prepared by method (A), a compound of formula (II) ashereinbefore defined is reacted with a compound of formula (IIIa)

wherein A, B, Z, q and r are as hereinbefore defined and R^(1′)-R^(6′)and Y′ represent R¹ to R⁶ and Y as hereinbefore defined or are groupsthat may be readily convertible to R¹ to R⁶.

The present invention also provides a general process (B) for preparingcompounds of formula (I) wherein Z is a bond, which process comprises:

reacting a compound of formula (IV)

wherein X is a leaving group, such as iodo, bromo or triflate, and A, B,q, r and Y are as hereinbefore defined and R^(1′)—R^(3′) represent R¹ toR³ as hereinbefore defined or are groups that may be readily convertibleto R¹ to R³,

with an aryl boronic acid of formula (V)

wherein R^(4′) represents R⁴ as hereinbefore defined or is a group thatmay be readily convertible to R⁴, under standard Suzuki conditions, e.g.treatment of compound (IV) with 4-chlorobenzeneboronic acid in toluenecontaining aqueous sodium carbonate and a catalytic amount of Pd(PPh₃)₄,at reflux under argon.

According to a further aspect of the invention, when compounds of theformula (ID) are prepared by method (B), a compound of formula (IVa)

wherein X is a leaving group, such as iodo, bromo or triflate, and A, B,q, r and Y are as hereinbefore defined and R^(1′)—R^(6′) represent R¹ toR⁶ as hereinbefore defined or are groups that may be readily convertibleto R¹ to R⁶,

with an aryl boronic acid of formula (V) as hereinbefore defined.

The present invention also provides a general process (C) for preparingcompounds of formula (I) which process comprises:

converting a compound of formula (I)

wherein A, B, Z, Y, q, r and R¹ to R⁴ are as hereinbefore defined, intoanother compound of formula (I) by substituting the group R¹ or thegroup R³ using conventional techniques.

Interconversion of one of the R^(1′) to R^(4′) groups to thecorresponding R¹ to R⁴ groups typically arises when one compound offormula (I) is used as the immediate precursor of another compound offormula (I), or when it is easier to introduce a more complex orreactive substituent at the end of a synthetic sequence.

For example, conversion of R^(1′) from a t-butoxycarbonyl (BOC) group tohydrogen is conducted by the treatment of the N-BOC protected compoundwith hydrogen chloride in ethanol or dioxan at room temperature.

Conversion of R^(1′) from hydrogen to an alkyl group is conducted by thetreatment of the NH compound with the appropriate aldehyde indichloroethane in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, or by the treatment of the NH compound with theappropriate alkyl halide, such as iodomethane, under standard alkylationconditions (potassium carbonate in DMF at 60° C.).

Conversion of R^(3′) from hydrogen to an alkyl group is conducted by thetreatment of the sulfonamide NH compound with the appropriate alcohol,such as methanol, under Mitsunobu conditions i.e. treatment withdiisopropyl azodicarboxylate/triphenylphosphine and methanol intetrahydrofuran at room temperature.

Compounds of formula (II) are known in the literature or may be preparedby known processes, for example, reduction of the corresponding nitrocompound as disclosed in WO 99/14197, or by procedures analogous tothese procedures. Suitable examples of an R^(1′) protecting group aretrifluoroacetyl or the t-butoxycarbonyl (BOC) group.

Compounds of formula (III) are commercially available or may be preparedby established procedures, for example chlorosulfonylation of a suitablesubstituted aromatic precursor, using chlorosulfonic acid, for exampleas described in J. Med. Chem., 2000, 43, 156-166.

Compounds of formula (IV) may be prepared from compounds of formula (II)by the treatment with the appropriate 4-substituted benzenesulfonylchloride using standard conditions, for example in pyridine ordichloromethane in the presence of a base such as triethylamine at roomtemperature.

Compounds of formula (V) are commercially available or may be preparedby known methodology, for example lithiation of a suitable substitutedbromobenzene at low temperature followed by quenching withtri-isopropylborate and acidic hydrolysis of the reaction product.

Compounds of formula (I) have been found to exhibit affinity fordopamine receptors, in particular the D₃ and D₂ receptors, and areuseful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions. Many of the compounds offormula (I) have also been found to have greater affinity for dopamineD₃ than for D₂ receptors. The therapeutic effect of currently availableantipsychotic agents (neuroleptics) is generally believed to be exertedvia blockade of D₂ receptors; however this mechanism is also thought tobe responsible for undesirable extrapyramidal side effects (eps)associated with many neuroleptic agents. Without wishing to be bound bytheory, it has been suggested that blockade of the dopamine D₃ receptormay give rise to beneficial antipsychotic activity without significanteps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; andSchwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314,1993). Additionally, certain compounds of formula (I) have antagonistaffinity for the serotonin 5-HT_(2A), 5-HT_(2C) and 5-HT₆ receptors.These additional properties may give rise to enhanced anti-psychoticactivity (e.g. improved effects on cognitive dysfunction) and/or reducedeps. These could include, but are not limited to, attenuation ofcognitive symptoms via 5-HT₆ receptor blockade (see Reavill, C. andRogers, D. C., 2001, Investigational Drugs 2, 104-109), and reducedanxiety (see for example Kennett et al., Neuropharmacology 1997April-May; 36 (4-5): 609-20), protection against eps (Reavill et al.,Brit. J. Pharmacol., 1999; 126: 572-574) and antidepressant activity(Bristow et al., Neuropharmacology 39:2000; 1222-1236) via 5-HT_(2C)receptor blockade.

Compounds of formula (I) may also exhibit affinity for other receptorsnot mentioned above, resulting in beneficial antipyschotic activity.

The compounds of formula (I) are of use as antipsychotic agents forexample in the treatment of schizophrenia, schizo-affective disorders,schizophreniform diseases, psychotic depression, mania, acute mania,paranoid and delusional disorders. Furthermore, they may have utility asadjunct therapy in Parkinsons Disease, particularly with compounds suchas L-DOPA and possibly dopaminergic agonists, to reduce the side effectsexperienced with these treatments on long term use (e.g. see Schwartz etal., Brain Res. Reviews, 1998, 26, 236-242). From the localisation of D₃receptors, it could also be envisaged that the compounds could also haveutility for the treatment of substance abuse where it has been suggestedthat D3 receptors are involved (e.g. see Levant, 1997, Pharmacol. Rev.,49, 231-252). Examples of such substance abuse include alcohol, cocaine,heroin and nicotine abuse. Other conditions which may be treated by thecompounds include dyskinetic disorders such as Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias; depression;anxiety; agitation; tension; social or emotional withdrawal in psychoticpatients; cognitive impairment including memory disorders such asAlzheimer's disease; psychotic states associated with neurodegenerativedisorders, e.g. Alzheimer's disease; eating disorders; obesity; sexualdysfunction; sleep disorders; emesis; movement disorders;obsessive-compulsive disorders; amnesia; aggression; autism; vertigo;dementia; circadian rhythm disorders; and gastric motility disorderse.g. IBS. Therefore, the invention provides a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof for use in therapy.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in acondition which requires modulation of a dopamine receptor.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt or solvate thereof foruse in the treatment of psychotic disorders, Parkinsons disease,substance abuse, dyskinetic disorders, depression, bipolar disorder,anxiety, cognitive impairment, eating disorders, obesity, sexualdysfunction, sleep disorders, emesis, movement disorders,obsessive-compulsive disorders, amnesia, aggression, autism, vertigo,dementia, circadian rhythm disorders and gastric motility disorders.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for the treatment of acondition which requires modulation of a dopamine receptor.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for the treatment ofpsychotic disorders, Parkinsons disease, substance abuse, dyskineticdisorders, depression, bipolar disorder, anxiety, cognitive impairment,eating disorders, obesity, sexual dysfunction, sleep disorders, emesis,movement disorders, obsessive-compulsive disorders, amnesia, aggression,autism, vertigo, dementia, circadian rhythm disorders and gastricmotility disorders.

The invention also provides a method of treating a condition whichrequires modulation of a dopamine receptor, which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I) as hereinbefore described or a pharmaceuticallyacceptable salt or solvate thereof.

In a further aspect, the invention provides a method of treatingpsychotic disorders, Parkinsons disease, substance abuse, dyskineticdisorders, depression, bipolar disorder, anxiety, cognitive impairment,eating disorders, obesity, sexual dysfunction, sleep disorders, emesis,movement disorders, obsessive-compulsive disorders, amnesia, aggression,autism, vertigo, dementia, circadian rhythm disorders and gastricmotility disorders which comprises administering to a mammal in needthereof an effective amount of a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt or solvate thereof.

A preferred use for dopamine antagonists according to the presentinvention is in the treatment of psychotic disorders, Parkinsonsdisease, substance abuse, dyskinetic disorders, depression, bipolardisorder, anxiety and cognitive impairment.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) as hereinbeforedescribed or a pharmaceutically (i.e. physiologically) acceptable saltthereof and a pharmaceutically (i.e. physiologically) acceptablecarrier. The pharmaceutical composition can be for use in the treatmentof any of the conditions described herein.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of formula (I) as hereinbefore described and theirpharmaceutically acceptable salts which are active when given orally canbe formulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochlorohydrocarbon. The aerosol dosageforms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, preferably between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof calculated as the free base, the compound being administered 1to 4 times per day. Suitably the compounds will be administered for aperiod of continuous therapy, for example for a week or more.

Biological Test Methods

Binding Experiments on Cloned Dopamine (e.g. D₂ and D₃) Receptors

The ability of the compounds to bind selectively to human D₂/D₃ dopaminereceptors can be demonstrated by measuring their binding to clonedreceptors. The inhibition constants (K_(i)) of test compounds fordisplacement of [¹²⁵I]-Iodosulpride binding to human D₂/D₃ receptorsexpressed in CHO cells were determined as follows. The cell lines wereshown to be free from bacterial, fungal and mycoplasmal contaminants,and stocks of each were stored frozen in liquid nitrogen. Cultures weregrown as monolayers or in suspension in standard cell culture media.Cells were recovered by scraping (from monolayers) or by centrifugation(from suspension cultures), and were washed two or three times bysuspension in phosphate buffered saline followed by collection bycentrifugation. Cell pellets were stored frozen at −80° C. Crude cellmembranes were prepared by homogenisation followed by high-speedcentrifugation, and characterisation of cloned receptors achieved byradioligand binding.

Preparation of CHO Cell Membranes

Cell pellets were gently thawed at room temperature, and resuspended inabout 20 volumes of ice-cold Extraction buffer; 5 mM EDTA, 50 mM Trizmapre-set crystals (pH7.4@37° C.), 1 mM MgCl₂, 5 mM KCl and 120 mM NaCl.The suspension was homogenised using an Ultra-Turrax at fall speed for15 seconds. The homogenate was centrifuged at 18,000 r.p.m for 15 min at4° C. in a Sorvall RC5C centrifuge. Supernatant was discarded, andhomogenate re-suspended in extraction buffer then centrifugation wasrepeated. The final pellet was resuspended in 50 mM Trizma pre-setcrystals (pH 7.4 @ 37° C.) and stored in 1 ml aliquot tubes at −80° C.(D2=3.0E+08 cells, D3=7.0E+07 cells and D4=1.0E+08 cells). The proteincontent was determined using a BCA protocol and bovine serum albumin asa standard (Smith, P. K., et al., Measurement of protein usingbicinchoninic acid. Anal. Biochem. 150, 76-85 (1985)).

Binding Experiments

Binding Experiments on D₃/D₂ Receptors

Crude D₂/D₃ cell membranes were incubated with 0.03 nM[¹²⁵I]-Iodosulpride (˜2000 Ci/mmol; Amersham, U. K., and the testcompound in a buffer containing 50 mM Trizma pre-set crystals (pH 7.4 @37° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.3% (w/v)bovine serum albumin. The total volume is 0.2 ml and incubated in awater bath at 37° C. for 40 minutes. Following incubation, samples werefiltered onto GF/B Unifilters using a Canberra Packard Filtermate, andwashed four times with ice-cold 50 mM Trizma pre-set crystals (pH 7.4 @37° C.). The radioactivity on the filters was measured using a CanberraPackard Topcount Scintillation counter. Non-specific binding was definedwith 10 μM SKF-102161 (YM-09151). For competition curves, 10 serial logconcentrations of competing cold drug were used (Dilution range: 10μM-10 μM). Competition curves were analysed using Inflexion, aniterative curve fitting programme in Excel. Results were expressed aspK_(i) values wherepK_(i)=−log10[Ki].

The exemplified compounds have pK_(i) values within the range of 6.6-9.6at the dopamine D₃ receptor.

The exemplified compounds have pK_(i) values within the range of 5.3-9.3at the dopamine D₂ receptor.

Binding Experiments on Cloned 5-HT₆ Receptors

Compounds were tested following the procedures outlined in WO 98/27081.All of the exemplified compounds have pK_(i) values within the range of7.0-8.8 at the serotonin 5-HT₆ receptor.

Binding Experiments on Cloned 5-HT₆ Receptors

Compounds were tested following the procedures outlined in WO 94/04533.All of the exemplified compounds have pK_(i) values within the range of6.6-8.4 at the serotonin 5-HT_(6C) receptor.

Binding Experiments on Cloned 5-HT_(2A) Receptors

Compounds can be tested following the procedures outlined in BritishJournal of Pharmacology (1996) 117, 427-434. All of the exemplifiedcompounds have pKi values within the range of 6.3-8.9 at the serotonin5-HT_(2A) receptor.

The invention is further illustrated by the following non-limitingexamples:

DESCRIPTION 11-(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone(D1)

7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (D1a)

1,2,4,5-Tetrahydro-3H-benzazepine (1 g) (See P. Ruggli et al., Helv.Chim. Acta, 18, 1388, [1935]) was added slowly dropwise to stirredfuming nitric acid (25 ml) at −10° C. Stirring was continued at −10° C.for 1 hour and the reaction mixture was then poured onto ice, theprecipitate collected by filtration and dried to give the title compoundas the nitrate salt, 1.4 g. This salt was suspended in water, cooled to5° C. and neutralised with 5M sodium hydroxide. The precipitate wascollected by filtration, recrystallised from water and dried, affordingthe title compound D1a as a white solid (0.6 g).

1-(7-Nitro-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone(D1b)

The 7-nitro benzazepine derivative (5 g) was dissolved indichloromethane (80 ml) and to this was added diisopropylethylamine (5.4ml) in dichloromethane (20 ml) at 0° C., followed by a solution oftrifluoroacetic anhydride (4.3 ml) in dichloromethane (20 ml) at 0° C.The mixture was allowed to warm to room temperature and stirredovernight. Aqueous work up with water and dichloromethane gave the titlecompound D1b (7.0 g). MH⁺ 289

1-(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone(D1)

The nitro derivative D1b was hydrogenated in accordance with theprocedure described in D2c to give the title compound D1. M⁺ 259

DESCRIPTION 2 7-Amino-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline(D2)

N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide (D2a)

A solution of trifluoroacetic anhydride (10.6 ml) in dichloromethane(100 ml) was added dropwise to a stirred solution of 2,6-lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2 g; 75 mmol) at 0° C.The mixture was stirred at 25° C. overnight under argon and then washedwith dilute citric acid (2×), brine and dried over Na₂SO₄. The materialin the organic phase gave the title compound D2a as a pale yellow solid(19.04 g).

7-Nitro-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline (D2b)

The nitro compound D2a (2.26 g; 9.15 mmol) and paraformaldehyde (0.45 g;14.4 mmol) in acetic acid (10 ml) and conc. H₂SO₄ (15 ml) were stirredat 25° C. for 20 h according to the procedure of G. E. Stokker., Tet.Lett., 1996, 37, 5453. Work up afforded the title compound D2b as awhite solid (2.17 g). ¹H NMR (CDCl₃) δ: 3.10 (2H, m), 3.92 (2H, m),4.85+4.92 (2H, 2 xs), 7.38 (1H, t), 8.10 (2H, m). ^(m)/_(z) (EI): 274(M⁺).

7-Amino-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline (D2)

The 7-nitro compound D2b (0.99 g, 3.6 mmol) in ethanol (50 ml) washydrogenated over 10% palladium on carbon (450 mg) at atmosphericpressure for 4 h. The catalyst was removed by filtration through a padof celite and evaporation gave the title compound D2 as a colourlesssolid (840 mg). ¹H NMR (CDCl₃) δ: 2.84 (2H, t), 3.23 (2H, bs), 3.82 (2H,m), 4.66 (2H, d), 6.47 (1H, m), 6.57 (1H, m), 6.96 (1H, m).

DESCRIPTION 3 7-Amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D3)

The title compound D3 was prepared using a similar methodology to thatdescribed in EP 284384. MH⁺ 263

DESCRIPTION 47-Amino-2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (D4)

7-Nitro-1,2,3,4-tetrahydroisoquinoline (D4a)

The trifluoroacetamide D2b (17.22 g; 63 mmol) was hydrolysed at roomtemperature using a solution of potassium carbonate (46.6 g) in 10%aqueous methanol (660 ml). Work-up with dichloromethane gave the titlecompound D4a (11 g).

7-Amino-2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (D4)

The title compound D4 was prepared from the compound D4a usingdi-t-butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25° C.followed by catalytic hydrogenation according to the procedure describedfor D2c. MH⁺ 249.

DESCRIPTION 57-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D5)

7-Methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butylester (D5a)

To a solution of 7-hydroxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylicacid tert-butyl ester (5 g, 19 mmol) in dimethylformamide (50 ml) wasadded potassium carbonate (3.4 g, 25 mmol) and methyl iodide (3.25 ml,60 mmol). The mixture was heated to 30° C. for 12 h. The solvent wasevaporated and the residue partitioned between dichloromethane (100 ml)and water (100 ml). The organic layer was separated and evaporated togive the crude product D5a as a colourless oil (5.3 g, 100%).

7-Methoxy-8-nitro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D5b)

To a mixture of 7-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylicacid tert-butyl ester (D5a) (5.3 g, 19 mmol) in glacial acetic acid (100ml) and acetic anhydride (10 ml) at 0° C. was added a mixture of nitricacid (70% aqueous, 5 g, 55 mmol) dropwise in glacial acetic acid (100ml) and acetic anhydride (10 ml) maintaining the temperature below 5° C.The mixture was stirred at room temperature for 2 h and then poured intoice/water (500 ml). The aqueous was extracted with dichloromethane(2×200 ml) and the combined organic portions were neutralised withsaturated sodium bicarbonate solution. The dichloromethane layer wasevaporated and the residue chromatographed on silica gel (eluent:hexane/dichloromethane (1:1) to dichloromethane) to give the product D5bas a colourless solid (1.5 g, 25%).

7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D5)

To a solution of7-methoxy-8-nitro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester D2b (1.5 g, 4.7 mmol) in ethanol (80 ml) was addedpalladium on charcoal (10%, 0.5 g). The mixture was stirred under anatmosphere of hydrogen for 2 h and then filtered. The solvent wasevaporated to give the title compound D5 as a colourless solid (1.35 g,100%).

Mass spectrum AP⁺: Found 193 ([M-Boc]⁺). C₁₆H₂₄N₂O₃ requires 292. ¹H NMR(CDCl₃) δ1.48 (9H, s), 2.76 (4H, m), 3.51 (4H, m), 3.65 (2H, s), 3.82(3H, s), 6.50 (1H, m), 6.56 (1H, m).

DESCRIPTION 6 5-Amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester (D6)

5-Nitroisoindoline nitrate (D6a)

Isoindoline (4 g, 33.1 mmol) was added to 95%. sulphuric acid, thereaction was treated carefully with fuming nitric acid (2.2 ml) at 0° C.and stirred for 1 h, then the mixture was poured onto ice and theresulting precipitate was collected by filtration and dried in vacuo toafford the title compound D6a (4.1 g, 46%); ¹H NMR (DMSO-d⁶) 8.35 (1H,s), 8.35 (1H, d, 8.4 Hz), 7.70 (1H, d, 8.4 Hz), 4.64 (4H,s).

5-Nitro-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (D6b)

The compound D6a (3.06 g, 13.47 mmol) in dichloromethane (50 ml) wastreated with triethylamine (4.09 g, 40.42 mmol) followed by di-tertbutyldicarbonate (3.08 g, 14.15 mmol) and stirred at room temperature for 3days. The reaction was then diluted with dichloromethane and washed with3N citric acid, sodium bicarbonate solution, water and brine. Theorganic phase was separated, dried over anhydrous sodium sulfate andevaporated in vacuo to afford the title compound D6b (3.5 g, 98%); ¹HNMR (CDCl₃) 8.19 (2H, m), 7.26 (1H, m), 4.75 (4H, m), 1.52 (9H, s).

5-Amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (D6)

The compound D6b (3.5 g, 13.25 mmol) was dissolved in ethanol (200 ml)and treated with 10 wt % Palladium on charcoal (1 g), and stirred under1 atm of H₂ for 16 hours. The reaction was filtered and evaporated invacuo to afford the title compound D6 (3.01 g, 96%);

MS (ES+), m/e 235 [MH]⁺.¹H NMR: δ CDCl₃ 1.52 (9H, s), 4.74 (2H, s), 4.77(2H, s), 7.4 (1H, m), 8.2 (2H, m).

DESCRIPTION 77-(4-Iodo-benzenesulfonylamino)-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylicacid tert-butyl ester (D7)

To a solution of D3 (4.7 g, 18 mmol) in pyridine (40 ml) at 0° C. wasadded dropwise a solution of 4-iodophenylsulfonyl chloride (6.1 g, 20mmol) in dichloromethane (20 ml). The reaction mixture was then stirredat room temperature for 18 h, then poured onto brine. This mixture wasextracted with ethyl acetate (3×), and the combined organic layerswashed with citric acid solution, sodium bicarbonate solution thenbrine. The organic layer was dried over sodium sulfate then evaporatedto afford the crude product. Chromatography on silica, eluting with20-50% ethyl acetate/hexane afforded the title compound D7 (8 g). MH⁺529

DESCRIPTION 8 4′-Chloro-biphenyl-4-sulfonyl chloride (D8)

The title compound D8 was prepared from 4-chlorobiphenyl bychlorosulfonation with chlorosulfonic acid using the classical procedure(J. Med. Chem. 2000, 43, 156-166).

DESCRIPTION 9 4′-Chloro-2-methyl-biphenyl-4-ylamine hydrochloride (D9)

A mixture of 4-chlorophenyl boronic acid (6.32 g),3-methyl-4-bromoaniline (5 g), toluene (135 ml), ethanol (40 ml) andpotassium carbonate solution (40 ml) was degassed and then stirred underan atmosphere of argon. Tetrakis(triphenylphosphine)palladium(O) (0.62g) was added and the mixture was stirred at reflux for 18 hours. Themixture was treated with water and ethyl acetate, then the organic layerwas separated, washed with brine and evaporated. The residue waschromatographed on silica eluted with 10% ethyl acetate in hexane, andtreated with hydrogen chloride in ether to give the title compound D9 asa white solid. ¹H NMR: δ DMSO-d⁶ 2.23 (3H, s), 7.2 (3H, m), 7.4 (2H, d),7.5 (2H, d)

DESCRIPTION 10 4′-Chloro-2-methyl-biphenyl4-sulfonyl chloride (D10)

A stirred suspension of 4′-chloro-2-methyl-biphenyl-4-ylaminehydrochloride D9 (2.76 g) was cooled to −5° C. and treated with asolution of sodium nitrite (1.2 g) in water (10 ml). The resultingsolution was stirred for 30 minutes, treated with urea (0.3 g) thenadded to a suspension of cuprous chloride (1 g) in acetic acid (30 ml)which had been saturated with sulfur dioxide stirred at 5° C. Thesolution was allowed to warm to room temperature over 1 hour, thenheated to 40° C. for 30 minutes. Extraction with dichloromethane andchromatography on silica eluted with 5% ethyl acetate in hexane gave thetitle compound D10 as a white solid (1.65 g) ¹H NMR: δ CDCl₃ 2.37 (3H,s), 7.2 (2H, m), 7.4 (3H, m), 7.9 (2H, m).

DESCRIPTION 117-Amino-8-ethoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D11)

The title compound D11 was prepared in accordance with Description 5,but methyl iodide was replaced with ethyl iodide for the alkylation ofthe phenol ¹H NMR (CDCl₃) δ 6.55 (1H, s), 6.51 (1H, s), 4.03 (2H, q,J=7.0 Hz), 3.68 (2H, s), 3.51 (4H, m), 2.75 (4H, m), 1.48 (9H, s), 1.41(3H, t, J=7.0 Hz).

DESCRIPTION 127-Amino-8-isopropoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D12)

The title compound was prepared in accordance with Description 5, butmethyl iodide was replaced with isopropyl iodide for the alkylation ofthe phenol. ¹H NMR (CDCl₃) δ 6.57 (1H, s), 6.50 (1H, s), 4.46 (1H, sept,J=6.1 Hz), 3.68 (2H, s), 3.51 (4H, m), 2.74 (4H, m), 1.48 (9H, s), 1.33(6H, d, J=6.1 Hz).

DESCRIPTION 137-Amino-8-bromo-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D13)

The aniline D3 (5 g, 19 mmol) was dissolved in dry acetonitrile (100 ml)and the solution was cooled to −15 ° C. A solution of N-bromosuccinimide(1.03 eq, 19.6 mmol, 3.48 g, in 70 ml of dry acetonitrile) was addeddropwise at −15 ° C. to the solution containing the aniline, over 20min. After the addition, the reaction mixture was left to warm up toroom temperature for 10 min and then it was poured onto water/brine (150ml+15 ml). The aqueous was extracted with EtOAc (100 ml, 50 ml), theorganics were combined, dried over Na₂SO₄, filtered and the solvent wasevaporated to afford the crude product. Chromatography on silica elutingwith 5-30% EtOAc/n-hexane afforded the title compound D13 (1.3 g).M⁺-Boc)=241.

DESCRIPTION 147-Amino-8-chloro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D14)

To a stirred solution of D3 (10 g, 38 mmol) in acetonitrile (300 ml) at0° C. was added N-chlorosuccinimide (6.6 g, 49 mmol) portionwise over 10minutes. The resulting solution was stirred overnight at roomtemperature, then water (500 ml) and EtOAc (500 ml) were added. Theorganic layer was separated, dried over magnesium sulfate andconcentrated in vacuo to give a dark brown oil. This oil was purified bycolumn chromatography using 20% diethyl ether/hexane as the eluant togive the title compound D14 as an orange glassy solid. (MH-Boc)⁺ 197.1,199.1

DESCRIPTION 157-Amino-8-ethyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D15)

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D15a)

The title compound was prepared according to the procedure described inWO 00/21951 i.e. 7-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g) in48% aqueous hydrobromic acid (350 ml) was allowed to stir at 100° C. for4 h. The mixture was allowed to cool to 20° C. then evaporated todryness, giving the crude hydroxy compound as a brown solid (14.5 g).This solid was dissolved in tetrahydrofuran (100 ml) and water (70 ml)and triethylamine (8 g) was added dropwise, followed by a solution ofdi-tert-butyl dicarbonate (14 g) in tetrahydrofuran (20 ml). Theresulting mixture was allowed to stir at 20° C. for 16 h thenpartitioned between ethyl acetate (200 ml) and water (200 ml). Theaqueous layer was extracted with ethyl acetate (100 ml). The combinedorganic extracts were washed with saturated aqueous sodium bicarbonate(100 ml), dried over anhydrous sodium sulfate and evaporated to dryness.The resulting oil was purified by chromatography over silica gel,eluting with 10-30% ethyl acetate in hexane, affording the titlecompound D15a as a white solid (8 g), MS (API⁺): Found 164 (MH⁺-Boc).C₁₅H₂₁NO₃ requires 263. ¹H NMR: δ CDCl₃ 1.48 (9H, s), 2.75-2.87 (4H, m),3.40-3.60 (4H, m), 4.95 (1H, s), 6.50-6.62 (2H, m), 6.96 (1H, d).

7-Hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D15b)

Nitration of D15a was carried out by adding 70% aqueous nitric acid (8g) dissolved in glacial acetic acid (100 ml)/acetic anhydride (10 ml) tothe phenol D15a (20 g) dissolved in AcOH (200 ml)/acetic anhydride (20ml) at 0° C. Aqueous work-up followed by chromatography on silica gelusing 0-20% EtOAc/n-hexane as eluant afforded the title compound D15b(11 g). ¹H NMR (CDCl₃) δ 7.85 (1H, s), 6.93 (1H, s), 3.56 (4H, m), 2.91(4H, m), 1.48 (9H, m).

7-Nitro-8-trifluoromethanesulfonyloxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D15c)

D15b (8.4 g) was dissolved in acetone (300 ml) and cooled to 0° C.Trifluoromethanesulfonyl chloride (4.4 ml) was added and the resultantmixture stirred at room temperature for 2 h. Evaporation in vacuofollowed by basic aqueous work-up afforded the title compound D15c (12g). ¹H NMR (CDCl₃) δ 7.95 (1H, s), 7.19 (1H, s), 3.61 (4H, m), 3.02 (4H,m), 1.48 (9H, m).

7-Nitro-8-vinyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D15d)

A mixture of D15c (500 mg ), vinyl tri-n-butyltin (0.4 ml), lithiumchloride (145 mg), palladium tetrakistriphenylphosphine (131 mg) and2,6-di-tert-butylphenol (4 mg ) in 1,4-dioxan (4 ml) was heated at 160°C. for 0.5 h in a sealed tube in a Smith microwave reactor. Aqueouswork-up followed by chromatography using 0-20% EtOAc/n-hexane as eluentgave the title compound D15d (260 mg).

7-Amino-8-ethyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D15)

Hydrogenation of D15d (260 mg) at 50 psi in ethanol (40 ml) over 10%palladium on charcoal (100 mg, paste) at room temperature afforded thetitle compound D15 (190 mg).

MH⁺291

DESCRIPTION 167-Amino-8-methyl-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D16)

7-Methyl-8-nitro-1,2,4,5-tetrahydro[d]azepine-3-carboxylic acidtert-butyl ester (D16a)

A mixture of D15c (1.0 g), tetramethyltin (0.6 ml), lithium chloride(0.29 g), palladium tetrakistriphenylphosphine (0.13 g) and2,6-di-tert-butylphenol (cat. ) in 1,4-dioxan (4 ml) was heated at 160°C. for 0.5 h in a sealed tube in a Smith microwave reactor. Aqueouswork-up followed by chromatography using 0-20% EtOAc/n-hexane as eluentgave the title compound D16a (0.44 g).

7-Amino-8-methyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D16)

Hydrogenation of D16a (440 mg) at 50 psi in ethanol (100 ml) over 10%palladium on charcoal (200 mg, paste) at room temperature afforded thetitle compound D16 (330 mg).

(MH-Boc)⁺ 177.

DESCRIPTION 177-Amino-8-ethylsulfanyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D17)

7-Nitro-8-ethylsulfanyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D17a)

A suspension of BINAP (106 mg), palladium(II) acetate (26 mg) andcaesium carbonate (556 mg) in dioxan (5 ml) was sonicated for 30 min atroom temperature. To the resulting red mixture was added D15c (0.5 g)and ethane thiol (0.2 ml) and the mixture was heated in a Smithmicrowave reactor for 30 mins at 160° C. The mixture was diluted withdiethyl ether (30 ml) and water (30 ml) and the layers were separated.The aqueous portion was extracted with a further portion of diethylether (10 ml) and the combined organic extracts were washed withsaturated sodium bicarbonate solution and then dried Na₂SO₄), filteredand evaporated. Chromatography using 0-10% EtOAc/n-hexane as eluent gavethe title compound D17a (0.23 g).

7-Amino-8-ethylsulfanyl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D17)

Hydrogenation of D17a (0.23 g) at 50 psi in ethanol (50 ml) over 10%palladium on charcoal (200 mg, paste) at room temperature afforded thetitle compound D17 (192 mg).

¹H NMR (CDCl₃) δ 7.12 (1H, s), 6.52 (1H, s), 4.23 (2H, m), 3.51 (4H, m),2.72 (6H, m), 1.48 (9H, m), 1.22 (3H, t, J=7.4 Hz).

DESCRIPTION 187-Amino-8-piperidin-1-yl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D18)

7-Nitro-8-piperidin-1-yl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D18a)

A suspension of BINAP (106 mg), palladium(II) acetate (26 mg) andcaesium carbonate (556 mg) in dioxan (5 ml) was sonicated for 30 min atroom temperature. To the resulting red mixture was added D15c (0.5 g)and piperidine (0.2 ml) and the mixture was heated in a Smith microwavereactor for 30 mins at 160° C. The mixture was diluted with diethylether (30 ml) and water (30 ml) and the layers were separated. Theaqueous portion was extracted with a further portion of diethyl ether(10 ml) and the combined organic extracts were washed with saturatedsodium bicarbonate solution and then dried (Na₂SO₄), filtered andevaporated. Chromatography using 0-10% EtOAc/n-hexane as eluent gave thetitle compound D18a (0.28 g).

7-Amino-8-piperidin-1-yl-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D18)

Hydrogenation of D18a (278 mg) at 50 psi in ethanol (40 ml) over 10%palladium on charcoal (100 mg, paste) at room temperature afforded thetitle compound D18 (253 mg). MH⁺ 346

DESCRIPTION 197-Amino-8-dimethylamino-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D19)

7-Nitro-8-dimethylamino-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D19a)

A suspension of BINAP (106 mg), palladium acetate (26 mg) and caesiumcarbonate (556 mg) in dioxan (5 ml) under argon was sonicated for 30 minat room temperature. To the resulting red suspension was added D15c (500mg) and dimethylamine hydrochloride (150 mg). The mixture was thenheated in a microwave reactor for 30 mins at 160° C., diluted withdiethyl ether (30 ml) and washed with water (50 ml) and saturated sodiumbicarbonate solution (30 ml) and then the layers separated. The organicportion was dried (Na₂SO₄), filtered and evaporated to give the titlecompound D19a as an oil (263 mg). MH⁺ 336

7-Amino-8-dimethylamino-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D19)

Hydrogenation of D19a at 50 psi in ethanol over 10% palladium oncharcoal at room temperature afforded the title compound D19. MH⁺ 306

DESCRIPTION 209-Chloro-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (D20)

3-Acetyl-7-nitro-1,2,4,5-tetrahydro-3-benzazepine (D20a)

The title compound was prepared according to a similar proceduredescribed in J. Heterocycl. Chem. 1971 8(5) 779.

3-Acetyl-7-nitro-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (D20b)

D20a (22.4 g) in trifluoromethane sulphonic acid (150 ml) was treatedwith N-iodosuccinimide (40 g) portionwise over 5 days. Aqueous workupgave the crude title compound D20b (25 g). MH⁺ 361.

7-Nitro-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (D20c)

Crude D20b (25 g) was heated to 120° C. in concentrated hydrochloricacid (1 liter) for 12 h. Basic aqueous workup followed by chromatographyusing 5% methanol/dichloromethane as eluent gave the title compound D20c(7 g). MH⁺ 319.

3-Methyl-7-nitro-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (D20d)

D20c (7.3 g) was treated with formalin (37% aqueous, 20 ml) indichloroethane (30 ml) for 0.5 h, followed by sodiumtriacetoxyborohydride (7 g). Chromatography using 1%methanol/dichloromethane as eluent and recrystallisation fromdichloromethane/hexane gave the title compound D20d (1.9 g). MH⁺ 333.

3-Methyl-7-nitro-9-chloro-1,2,4,5-tetrahydro-3-benzazepine (D20e)

Reaction of D20d (0.8 g) with copper(I) chloride (1.68 g) indimethylformamide (15 ml) at 120° C. for 2 h followed by chromatographyusing 1-3% methanol/dichloromethane as eluent gave the title compoundD20e (0.3 g). MH⁺ 241.

9-Chloro-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (D20)

Hydrogenation of D20e (0.3 g) at 1 atmosphere in ethanol over 10%rhodium on charcoal at room temperature afforded the title compound D20(0.19 g). MH⁺ 211.

DESCRIPTION 219-Bromo-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (D21)

3-Methyl-7-nitro-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (D21a)

The title compound was prepared according to the procedure described forD20d.

3-Methyl-7-nitro-9-bromo-1,2,4,5-tetrahydro-3-benzazepine (D21b)

Reaction of D21a (1 g) with copper(I) bromide (3 g) in dimethylformamide(10 ml) at reflux for 3 h followed by chromatography using 1-3%methanol/dichloromethane as eluent gave the title compound D21b (0.23g). MH⁺ 286.

9-Bromo-3-methyl-2,3,4,5-tetrahydro-1H-benzo [d]azepin-7-ylamine (D21)

Reduction of the nitro group was achieved by treating D21b (0.23 g) inethanol (6 ml), water (3 ml) and acetic acid (0.5 ml) with iron powder(180 mg) at reflux for 1 h. Basic aqueous workup and filtering gave thetitle compound D21 (0.19 g). MH⁺ 256.

DESCRIPTION 227-(4-Iodo-benzenesulfonylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D22)

7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester (D5) (1.9 g, 6.5 mmol) was treated with pipsyl chloride(2.2 g, 7.2 mmol) in dichloromethane (20 ml) and pyridine (35 ml). Themixture was stirred for 13 h and the solvents evaporated. Chromatographyon silica eluting with dichloromethane afforded the title compound D22(2.8 g). M⁺-C(CH₃)₃+2H=503. ¹H NMR (CDCl₃) δ 7.76 (2H, d, J=8.6 Hz),7.43 (2H, d, J=8.6 Hz), 6.81 (1H, s), 6.50 (1H, s), 3.58 (3H, s), 3.49(4H, m), 2.80 (4H, m), 1.47 (9H, s).

DESCRIPTION 237-[4-(4-Fluorobenzyl)benzenesulfonylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D23)

To a solution of the iodo compound D7 (0.129 g, 0.244 mmol, 1.0 eq) inanhydrous tetrahydrofuran (2 ml) under argon at room temperature wasadded dropwise 4-fluorobenzylzinc chloride (1.1 ml 0.5M intetrahydrofuran, 0.537 mmol, 2.2 eq). The resultant solution wasdegassed by bubbling argon through the solution for 5 min then Pd(PPh₃)₄was added and the solution heated at 50° C. for 4 h before allowing tocool to room temperature. Saturated aqueous NH₄Cl solution was added (10ml) and the mixture extracted with EtOAc (2×10 ml). The organic layerwas washed with brine (15 ml), dried over MgSO₄ and evaporated todryness. Purification by chromatography over silica gel, eluting with25% EtOAc-petrol afforded the title compound D23 as a pale yellow solid(0.120 g, 97%). MH⁺ 511. ¹H NMR δ CDCl₃ 1.47 (9H, s), 2.79 (4H, m), 3.48(4H, m), 3.97 (2H, s), 6.44 (1H, s), 6.81 (2H, br.s), 6.82-7.25 (5H, m),7.22 (2H, d), 7.67 (2H, d).

DESCRIPTION 244-(4-Fluorobenzyl)-N-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)benzenesulfonamidehydrochloride (D24)

A solution of the Boc-protected amine D23 (0.104 g, 0.204 mmol, 1.0 eq)in 1,4 dioxan (3 ml) and 4M HCl in dioxan (2 ml, excess) was stirred atroom temperature under argon for 6 h then evaporated to dryness,affording the desired compound D24 as a white solid (0.086 g, 96%). MH⁺411.

EXAMPLE 14-(4-Chloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E1)

4-(4-Chloro-phenyl)-N-[3-(2,2,2-trifluoro-ethanoyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-benzenesulfonamide(E1a)

A solution of 4′-chloro-biphenyl-4-sulfonyl chloride D8 (1.24 g, 4.3mmol) in dichloromethane 910 ml) was added dropwise to a solution of D1(1.0 g, 3.9 mmol) in pyridine (20 ml) at 0° C. The mixture was stirredat room temperature for 18 h, then poured onto brine and extracted withethyl acetate (2×). The combined organic layer was washed with citricacid, sodium bicarbonate solution and brine, then dried and evaporatedto afford the crude product. Chromatography on silica, eluting with 30%ethyl acetate/hexane afforded the product E1a (1.5 g). MH⁺ 509

4-(4-Chloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E1)

The compound E1a was dissolved in 2M ammonia in methanol (24 ml) andwater (6 ml) added to the stirred solution. Stirring was continued for18 h, then the solution evaporated to dryness. Application of the crudeproduct to an SCX ion exchange cartridge, followed by elution withmethanol followed by 1% ammonia in methanol afforded the title compoundE1 (0.85 g). MH⁺ 413. ¹H NMR: δ CDCl₃ 2.8-2.9 (8H, m), 6.8 (2H, m), 6.96(1H, d), 7.43 (2H, d), 7.50 (2H, d), 7.61 (2H, d), 7.81 (2H, d).

EXAMPLE 24-(4-Chloro-phenyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E2)

A solution of E1 (144 mg, 0.35 mmol) in dichloroethane (10 ml) wastreated with formalin (0.3 ml) followed by sodium triacetoxyborohydride(250 mg). The mixture was stirred for 18 h, then added to sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic extracts were washed with brine, dried and evaporated to affordthe crude product. Chromatography on silica, eluting with 2% methanol indichloromethane containing 0.5% aqueous ammonia, afforded the titlecompound E2 (140 mg). MH⁺ 425. ¹H NMR: δ CDCl₃ 2.35 (3H, s), 2.53 (4H,m), 2.86 (4H, m), 6.83 (2H, m), 6.96 (1H, d), 7.44 (2H, d), 7.51 (2H,d), 7.61 (2H, d), 7.81 (2H, d).

EXAMPLE 34-(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E3)

4-(4-Chloro-phenyl)-N-methyl-N-[3-(2,2,2-trifluoro-ethanoyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-benzenesulfonamide(E3a)

The trifluoroacetamide E1a (500 mg, 1 mmol) was dissolved in drytetrahydrofuran (15 ml) containing triphenylphosphine (330 mg) and drymethanol (200 mg). To this stirred solution was addeddi-isopropylazodicarboxylate (250 mg, 1.2 mmol) and the mixture stirredat room temperature for 18 h. The solvent was then evaporated and theresidue chromatographed on silica using 20% ethyl acetate/hexane aseluant to afford the product E3a (640 mg). MH⁺ 523.

4(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E3)

Deprotection of the compound D3a using a procedure similar to that forcompound E1b afforded the title compound E3 (370 mg). MH⁺ 427. ¹H NMR: δCDCl₃ 2.89 (8H, m), 3.18 (3H, s), 6.79 (1H, m), 6.91 (1H, s), 7.01 (1H,d), 7.46 (2H, d), 7.53 (2H, d), 7.65 (4H, s).

EXAMPLE 44-(4-Chloro-phenyl)-N-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E4)

The title compound was prepared from E3 using a procedure similar tothat for compound E2. MH⁺ 441. ¹H NMR: δ CDCl₃ 2.37 (3H, s), 2.57 (4H,s), 2.90 (4H, s), 3.18 (3H, s), 6.80 (1H, dd), 6.92 (1H, dd), 7.01 (1H,d), 7.45 (2H, d), 7.53 (2H, d), 7.63 (4H, s).

EXAMPLE 54-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E5)

7-(3′,4′-Dichloro-biphenyl-4-sulfonylamino)-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylicacid tert-butyl ester (E5a)

A solution of the iodo intermediate D7 (0.53 g, 1 mmol) was dissolved ina mixture of ethanol (3 ml), toluene (10 ml) and 2M aqueous potassiumcarbonate solution (3 ml) containing 3,4-dichlorobenzeneboronic acid(0.29 g, 1.5 mmol). This mixture was rigorously degassed and an argonatmosphere introduced. Tetrakis(triphenylphosphine)palladium (0.1 g) wasadded, and the mixture heated to 90° C. for 18 h. After cooling, thesolution was poured onto brine and extracted with ethyl acetate (2×).The organic layer was washed with brine dried and evaporated to affordthe crude product. Chromatography on silica, eluting with 10-25% ethylacetate/hexane afforded the title compound E5a (0.57 g). MH⁺ 548.

4-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E5)

The title compound was prepared from compound E5a by treatment with asolution of ethanolic hydrogen chloride, followed by the addition ofether to precipitate the product E5. MH⁺ 447. ¹H NMR: δ DMSO 2.98 (4H,s), 3.08 (4H, s), 6.95 (2H, m), 7.06 (1H, d), 7.74 (2H, m), 7.8-7.9 (4H,m), 8.01 (1H, dd).

EXAMPLE 64-(4-Chloro-phenyl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E6)

The title compound E6 was prepared from D5 and D8 using a proceduresimilar to that for compounds E1a and E5b. MH⁺ 443. ¹H NMR DMSO δ: 3.00(4H, m), 3.11 (4H, m), 3.40 (3H, s), 6.79 (1H, s), 7.09 (1H, s), 7.56(2H, d, J=8.5 Hz), 7.74 (2H, d, J=7.1 Hz), 7.77 (2H, d, J=7.1 Hz), 7.83(2H, d, J=8.5 Hz), 9.14 (2H, s), 9.53 (1H, s)

EXAMPLE 74-(4-Chloro-phenyl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E7)

The title compound was prepared from E6 using a procedure similar tothat for E2, and the product isolated as the hydrochloride salt. MH⁺457. ¹H NMR:δCDCl₃ 2.35 (3H, s), 2.50 (4H, m), 2.84 (4H, m), 3.57 (3H,s), 6.48 (1H, s), 6.9 (1H, b s), 7.31 (1H, s), 7.4-7.59 (6H, m), 7.80(2H, m).

Examples 11-41 and 74-154 and 188-209 and 216-217 were prepared usinganalogous procedures to Examples 1-7 and 42-47 using the appropriatestarting materials, with the products being isolated as either the freebases or hydrochloride salts. All ¹H NMR are consistent with thestructures shown.

EXAMPLE 84-(4-Chloro-phenyl)-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide(E8)

The title compound E8 was prepared from D4 and D8 using a proceduresimilar to that for compounds E1a and E5b. MH⁺ 399. ¹H NMR: δ DMSO-d⁶2.5 (2H,m), 2.8 (2H,m), 3.7 (2H, m), 6.77 (1H, ms), 6.9 (2H, m), 7.5(2H, d), 7.7 (2H, d), 7.8(4H, m).

Examples 48-73 and 155-166 were prepared using analogous procedures toExamples 1-8 using the appropriate starting materials, with the productsbeing isolated as either the free bases or hydrochloride salts. All ¹HNMR are consistent with the structures shown.

EXAMPLE 94-(4-Chloro-phenyl)-N-(2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamidehydrochloride (E9)

The title compound E9 was prepared from D6 and D8 using a proceduresimilar to that for compounds E1a and E5b. MH⁺ 385. ¹H NMR: δ DMSO-d⁶4.4 (4H, m), 7.11 (1H, d), 7.25 (2H, m), 7.55 (2H, d), 7.73 (2H, m),7.86 (4H, s), 9.7 (2H, m), 10.55 (1H, m).

EXAMPLE 104-(4-Chloro-phenyl)-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide(E10)

The title compound E10 was prepared from E9 using a procedure similar tothat for compound E2. MH⁺ 399. ¹H NMR: δ DMSO-d⁶ 0.86 (3H, m), 1.2 (2H,m), 1.5 (2H, m), 2.41 (3H, s) 2.6 (2H, m), 3.68 (4H, s), 6.87 (IH, d),6.93 (1H, s), 7.05 (2H, d), 7.32 (2H, d), 7.64 (2H, d).

Examples 167-174 were prepared using analogous procedures to Examples9-10, and as described herein, using the appropriate starting materials,with the products being isolated as either the free bases orhydrochloride salts. All ¹H NMR are consistent with the structuresshown.

EXAMPLE 424-(4-Chloro-phenyl)-3-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E42)

The title compound E42 was prepared from D3 and D9 using a proceduresimilar to that for compounds E1a and E5b. MH⁺ 427. ¹H NMR: δ DMSO-d⁶2.26 (3H,s), 3.0 (4H, m), 3.15 (4H, m), 6.95 (2H, m), 7.07 (1H, d), 7.4(3H, m), 7.5 (2H, d), 7.63 (1H, d), 7.74 (1H, s), 9.1 (1H, br). 10.3(1H, br)

EXAMPLE 434-(4-Chloro-phenyl)-3-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E43)

The title compound was prepared from E42 using a procedure similar tothat for compound E2. MH⁺ 441. ¹H NMR: δ CDCl₃ 2.24 (3H,s), 2.34 (3H,s),2.6 (4H, m), 2.8 (4H, m), 6.85 (2H, m), 7.0 (1H, d), 7.2 (3H, m),7.4(2H, m), 7.6 (2H, m).

EXAMPLE 444-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride (E44)

The title compound E44 was prepared from D5 and D10 using a proceduresimilar to for compounds E1a and E5b. MH⁺ 457. ¹H NMR: δ DMSO-d⁶ 2.51(3H, s), 3.23 (8H, b s), 3.69 (3H, s), 6.57 (1H, s), 6.98 (1H, s), 7.20(2H, m), 7.38 (3H, m), 7.60 (1H, d), 7.67 (1H, s).

EXAMPLE 454-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide(E45)

The title compound E44 was prepared from E46 using a procedure similarto that for compound E2. MH⁺ 471. ¹H NMR: δ CDCl₃ 2.23 (3H, s), 2.50(3H, s), 2.74 (4H, s), 2.99 (4H, s), 3.64 (3H, s), 6.52 (1H, s), 7.17(2H, d), 7.26 (1H, d), 7.31 (1H, s), 7.38 (2H, d), 7.41 (1H, m), 7.66(1H, m).

Examples 46-47 were prepared using analogous procedures to E44 and E45using the appropriate starting materials, with the products beingisolated as either the free bases or hydrochloride salts. All ¹H NMR areconsistent with the structures shown.

EXAMPLE 1074-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide(E107)

7-[4-(5-Chloro-thiophen-2-yl)-benzenesulfonylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (E107a)

7-(4-Iodo-benzenesulfonylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester D22 (0.28 g, 0.5 mmol) was treated with5-chloro-thiophene-2-boronic acid under standard Suzuki conditions (seeD9) followed by aqueous workup and chromatography to give the titlecompound E107a (0.22 g). M⁺-C(CH₃)₃+H=493/495.

4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamidehydrochloride (E107b)

7-[4-(5-Chloro-thiophen-2-yl)-benzenesulfonylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester E107a (0.22 g) was treated with 4M HCl in dioxansolution for 2 h. Diethyl ether was added and the precipitate filteredto give the title compound E107b as a colourless solid (0.19 g). M⁺447/449

4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide(E107)

4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide(E107b) (0.19 g) in dichloroethane (8 ml) was treated with triethylamine(0.9 ml) and formalin solution (37% aqueous, 0.3 ml) followed by sodiumtriacetoxyborohydride (250 mg). The mixture was shaken vigorously for 1h and then diluted with dichloromethane (5 ml) and sodium bicarbonatesolution (3 ml). The layers were separated and the organic portionevaporated. Chromatography on silica eluting with 10% methanol/dichloromethane afforded the title compound E107 (57 mg). M⁺ 463/465

¹H NMR (CDCl₃) δ 7.71 (2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.5 Hz), 7.29(1H, s), 7.15 (1H, d, J=3.9 Hz), 6.92 (1H, d, J=3.9 Hz), 6.86 (1H, s),6.48 (1H, s), 3.57 (3H, s), 2.88 (4H, m), 2.57 (4H, m), 2.39 (3H, s).

EXAMPLE 2164-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide(E216)

7-(4-Bromo-2-fluoro-benzenesulfonylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (E216a)

7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acidtert-butyl ester D5 (391 mg) was treated with2-fluoro-4-bromobenzenesulfonyl chloride (460 mg) in dichloromethane (15ml) and pyridine (9 ml). The mixture was stirred for 3 h and thesolvents evaporated. Chromatography on silica eluting withdichloromethane afforded the title compound E216a (740 mg). M−H 575

7-[2-Fluoro-4-(5-chloro-thiophen-2-yl)-benzenesulfonylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (E216b)

7-(4-Iodo-2-fluoro-benzenesulfonylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester E216a(320 mg) was treated with 5-chloro-thiophene-2-boronic acid (135 mg)under standard Suzuki conditions (see D9) followed by aqueous workup andchromatography to give the title compound E216b (140 mg). M−H 565

2-Fluoro-4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamidehydrochloride (E216c)

7-[2-Fluoro4-(5-chloro-thiophen-2-yl)-benzenesulfonylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (E216b) (140 mg) was treated with ethanolic HClsolution (6 ml) for 2 h. The solvent was evaporated to give the titlecompound E216c as a colourless solid (100 mg). M+H 445

4-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide(E216)

2-Fluoro-4-(5-chloro-thiophen-2-yl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamideE216c (100 mg) in dichloroethane (8 ml) was treated with formalinsolution (37% aqueous, 0.2 ml) followed by sodium triacetoxyborohydride(70 mg). The mixture was shaken vigorously for 1 h and then diluted withdichloromethane (5 ml) and sodium bicarbonate solution (5 ml). Thelayers were separated and the organic portion was evaporated.Chromatography on silica eluting with 10% methanol/dichloromethaneafforded the title compound E216. M+H 459. ¹H NMR (DMSO-d⁶) (HCl salt) δ10.78 (1H, s), 9.76 (1H, s), 7.79 (2H, d, J=11.5 Hz), 7.66 (1H, d, J=4Hz), 7.59 (1H, t, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.26 (1H, d, J=4 Hz),7.08 (1H, s), 6.81 (1H, s), 3.53 (2H, m), 3.42 (3H, s), 3.20 (2H, m),2.92 (4H, m), 2.77 (3H, d, J=4.6 Hz).

EXAMPLE 217 4′-Chloro-biphenyl-4-sulfonic acid(dimethylamino-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amide(E217)

7-(4′-Chloro-biphenyl-4-sulfonylamino)-8-dimethylamino-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid dimethyl-ethyl ester (E217a)

7-Amino-8-dimethylamino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylicacid tert-butyl ester (D19) (120 mg) was treated with4′-chlorobiphenyl4-sulfonyl chloride (136 mg) in dichloromethane (5 ml)and pyridine (0.05 ml). Mixture stirred for 3 h and the solventsevaporated. Chromatography on silica eluting with 20% ethylacetate/hexane afforded the title compound E217a (175 mg). M+H 556/558

4′-Chloro-biphenyl-4-sulfonic acid(8-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amidehydrochloride (E217b)

7-(4′-Chloro-biphenyl-4-sulfonylamino)-dimethylamino-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid dimethyl-ethyl ester (E217a) (175 mg) was treated with ethanolicHCl solution (4 ml) for 2 h. The solvent was evaporated to give thetitle compound E217b as a colourless solid (120 mg). M+H 456/458

4′-Chloro-biphenyl-4-sulfonic acid(dimethylamino-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amide(E217)

4′-Chloro-biphenyl-4-sulfonic acid(8-dimethylamino-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amidehydrochloride (E217b) (75 mg) in dichloroethane (3 ml) was treated withformalin solution (37% aqueous, 1 ml) followed by sodiumtriacetoxyborohydride (48 mg). The mixture was shaken vigorously for 1 hand then diluted with dichloromethane (10 ml) and sodium bicarbonatesolution (10 ml). The layers were separated and the organic portion wasevaporated. Chromatography on silica eluting with 10%methanol/dichloromethane afforded the title compound E217 (65 mg). M+H470/472. ¹H NMR (CDCl₃) δ 8.05 (1H, br s), 7.90 (2H, d, J=6.7 Hz), 7.60(2H, d, J=6.7 Hz), 7.47 (2H, d, J=6.4 Hz), 7.42 (2H, d, J=6.4 Hz), 7.35(1H, s), 6.83 (1H, s), 2.87 (2H, m), 2.81 (2H, m), 2.53 (4H, m), 2.40(6H, s), 2.35 (3H, s).

EXAMPLE 2104-(4-Fluorobenzyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)benzenesulfonamidehydrochloride (E210)

To a suspension of salt D24 (0.083 g, 0.186 mmol, 1.0 eq) in1,2-dichloroethane (3.5 ml) at room temperature was added triethylamine(26 μl, 0.186 mmol, 1.0 eq) followed by 37% aqueous formaldehydesolution (0.6 ml, excess). After vigorous stirring for 5 min. sodiumtriacetoxyborohydride (0.090 g, excess) was added portionwise. After 2 hsaturated aqueous sodium bicarbonate solution (10 ml) anddichloromethane (10 ml) were added and the layers separated. The organiclayer was evaporated to dryness, affording the free base as a paleyellow solid (0.077 g, 97%). The solid was dissolved in methanol, 1M HCladded (1.05 eq) and the mixture concentrated to dryness, giving thetitle compound E210 as an off-white solid. MH⁺ 425. ¹H NMR δ DMSO-d⁶2.43 (3H, s), 2.82 (4H, m), 3.51 (4H, m), 4.04 (2H, s), 6.93-7.35 (7H,m), 7.39 (2H, d), 7.73 (2H, d), 10.28 (1H, s), 10.75 (1H, s).

Examples 175-187 were prepared using analogous procedures to Example 188using the appropriate starting materials and Examples 211-215 usinganalogous procedures to Descriptions 23-24 and Example 210, with theproducts being isolated as either free bases or hydrochloride salts. All¹H NMR are consistent with the structures shown.

All of the compounds listed below in Table 1 relate to compounds of theformula (IJ): TABLE 1

Ex- ample R¹ R² R³ R⁴ R⁵ R⁶ Z MH⁺ 1 H H H 4-ClPh H H bond 413 2 Me H H4-ClPh H H bond 427 3 H H Me 4-ClPh H H bond 427 4 Me H Me 4-ClPh H Hbond 441 5 H H H 3,4-diClPh H H bond 447 6 H 8-MeO H 4-ClPh H H bond 4437 Me 8-MeO H 4-ClPh H H bond 457 11 H 8-Br H 4-ClPh H H bond 493 12 Me HH 2-ClPh H H bond 427 13 H H H 3-ClPh H H bond 413 14 Me H H 3-ClPh H Hbond 427 15 Me H H 3,4-diClPh H H bond 461 16 Me H H 2,4-diClPh H H bond461 17 H H H 4-BrPh H H bond 458 18 Me H H 4-BrPh H H bond 472 19 Me H H4-MePh H H bond 407 20 H H H 3-MePh H H bond 393 21 Me H H 3-MePh H Hbond 407 22 H H H 2-MePh H H bond 393 23 Me H H 2-MePh H H bond 407 24Me H H 4-CF₃Ph H H bond 461 25 Me H H 4-OCF₃Ph H H bond 477 26 Me H H4-MeSPh H H bond 439 27 Me H H 4-t-BuPh H H bond 449 28 H H H 4-CNPh H Hbond 405 29 Me H H 4-CNPh H H bond 419 30 Me H H 4-MeOPh H H bond 423 31Me H H 4-FPh H H bond 411 32 Me H H 2-thienyl H H bond 399 33 Me H H5-Cl-2-thienyl H H bond 434 34 H H H 3-thienyl H H bond 385 35 Me H H3-thienyl H H bond 399 36 Me H H 2-naphthyl H H bond 443 37 H H H2-benzofuranyl H H bond 419 38 H H H 4-pyridyl H H bond 379 39 Et H H4-ClPh H H bond 441 40 n-Pr H H 4-ClPh H H bond 455 41 i-Pr H H 4-ClPh HH bond 455 42 H H H 4-ClPh 3-Me H bond 427 43 Me H H 4-ClPh 3-Me H bond441 44 H 8-OMe H 4-ClPh 3-Me H bond 457 45 Me 8-OMe H 4-ClPh 3-Me H bond471 46 H 8-Br H 4-ClPh 3-Me H bond 506 47 Me 8-Br H 4-ClPh 3-Me H bond520 74 Me H H 4-NO₂Ph H H bond 438 75 H H H 3-furanyl H H bond 369 76 MeH H 3-furanyl H H bond 383 77 Me H H 4-ClPh H H O 443 78 H 8-MeO H Ph HH bond 409 79 Me 8-MeO H Ph H H bond 423 80 H 8-MeO H 3-ClPh H H bond443 81 Me 8-MeO H 3-ClPh H H bond 457 82 H 8-MeO H 3,4-diClPh H H bond478 83 Me 8-MeO H 3,4-diClPh H H bond 492 84 H 8-MeO H 2,4-dIClPh H Hbond 478 85 Me 8-MeO H 2,4-diClPh H H bond 492 86 H 8-MeO H 2-Me-4-ClPhH H bond 457 87 Me 8-MeO H 2-Me-4-ClPh H H bond 471 88 H 8-MeO H 4-FPh HH bond 427 89 Me 8-MeO H 4-FPh H H bond 441 90 H 8-MeO H 4-CF₃Ph H Hbond 477 91 Me 8-MeO H 4-CF₃Ph H H bond 491 92 H 8-MeO H 4-OCF₃Ph H Hbond 493 93 Me 8-MeO H 4-OCF₃Ph H H bond 507 94 H 8-MeO H 4-MeOPh H Hbond 439 95 Me 8-MeO H 4-MeOPh H H bond 453 96 H 8-MeO H 4-CNPh H H bond434 97 Me 8-MeO H 4-CNPh H H bond 448 98 H 8-MeO H 4-(NMe₂)Ph H H bond452 99 Me 8-MeO H 4-(NMe₂)Ph H H bond 466 100 H 8-MeO H Ph H H O 425 101Me 8-MeO H Ph H H O 439 102 H 8-MeO H 4-ClPh H H O 459 103 Me 8-MeO H4-ClPh H H O 473 104 H 8-MeO H 2-thienyl H H bond 415 105 Me 8-MeO H2-thienyl H H bond 429 106 H 8-Me0 H 5-Cl-2-thienyl H H bond 449 107 Me8-MeO H 5-Cl-2-thienyl H H bond 463 108 H 8-MeO H 3-thienyl H H bond 415109 Me 8-MeO H 3-thienyl H H bond 429 110 H 8-Me0 H 3-furanyl H H bond399 111 Me 8-MeO H 3-furanyl H H bond 413 112 H 8-MeO H 4-pyridyl H Hbond 410 113 Me 8-MeO H 4-pyridyl H H bond 424 114 H H H 4-ClPh 3-F Hbond 431 115 Me H H 4-ClPh 3-F H bond 445 116 H H H 4-ClPh 3-Cl H bond448 117 H 8-EtO H 4-ClPh H H bond 457 118 Me 8-EtO H 4-ClPh H H bond 471119 H 8-i-PrO H 4-ClPh H H bond 471 120 Me 8-i-PrO H 4-ClPh H H bond 485121 H 8-EtO H 4-ClPh 3-Me H bond 472 122 Me 8-EtO H 4-ClPh 3-Me H bond486 123 H 8-i-PrO H 4-ClPh 3-Me H bond 486 124 Me 8-i-PrO H 4-ClPh 3-MeH bond 500 125 H 8-i-PrO H 2-thienyl H H bond 443 126 H 8-i-PrO H3-thienyl H H bond 443 127 H 8-i-PrO H 3-furanyl H H bond 427 128 H8-i-PrO H 4-FPh H H bond 455 129 H 8-i-PrO H 4-MeOPh H H bond 467 130 H8-i-PrO H 4-CF₃OPh H H bond 521 131 H 8-i-PrO H 2-Me-4-ClPh H H bond 486132 H 8-i-PrO H 3-Me-4-ClPh H H bond 486 133 Me 8-i-PrO H 2-thienyl H Hbond 457 134 Me 8-i-PrO H 3-thienyl H H bond 457 135 Me 8-i-PrO H3-furanyl H H bond 441 136 Me 8-i-PrO H 4-FPh H H bond 469 137 Me8-i-PrO H 4-MeOPh H H bond 481 138 Me 8-i-PrO H 4-CF₃OPh H H bond 535139 Me 8-i-PrO H 2-Me-4-ClPh H H bond 500 140 Me 8-i-PrO H 3-Me-4-ClPh HH bond 500 141 Me 8-MeO H 4-ClPh 2-F H bond 475 142 Me 8-Br H 4-ClPh 2-FH bond 524 143 Me 8-MeO H 4-ClPh 3-F H bond 475 144 Me 8-MeO H 4-ClPh3-CF₃ H bond 525 145 H H i-Pr 4-ClPh H H bond 455 146 Me H i-Pr 4-ClPh HH bond 469 147 H H Me 3-thienyl H H bond 399 148 Me H Me 3-thienyl H Hbond 413 149 H H Me 4-CNPh H H bond 418 150 Me H Me 4-CNPh H H bond 432151 H 8-MeO i-Pr 4-ClPh H H bond 485 152 Me 8-MeO i-Pr 4-ClPh H H bond499 153 H 8-MeO Me 4-ClPh H H bond 457 154 Me 8-MeO Me 4-ClPh H H bond471429 175 Me 8-MeO H 5-Me-2-thienyl H H bond 443 176 Me 8-Br H5-Me-2-thienyl H H bond 492 177 Me 8-Br H 3,5-dimethylisoxazol-4-yl H Hbond 491 178 Me 8-Br ^(i)Pr 3,5-dimethylisoxazol-4-yl H H bond 533 179Me 8-Cl H 3,5-dimethylisoxazol-4-yl H H bond 446 180 Me 8-Cl ^(i)Pr3,5-dimethylisoxazol-4-yl H H bond 489 181 Me 8-H H 5-Me-2-furyl H Hbond 397 182 Me 8-Br H 5-Me-2-furyl H H bond 476 183 Me 8-Cl H5-Me-2-furyl H H bond 431 184 Me 8-MeO H 5-Me-2-furyl H H bond 427 185Me 8-MeO H 4-Me-2-thienyl H H bond 443 186 Me 8-H H N-Boc-2-pyrrolyl H Hbond 412 187 Me 8-MeO H N-Boc-2-pyrrolyl H H bond 512 188 H 8-Et H 4-FPhH H bond 425 189 Me 8-Et H 4-ClPh H H bond 456 190 Me 8-Et H 4-FPh H Hbond 439 191 Me H H 3,4-FPh H H bond 429 192 Me H H 2-FPh H H bond 411193 Me 8-Et iPr 2-FPh H H bond 481 194 Me 8-SEt H 4-ClPh H H bond 488195 Me 8-Me H 4-FPh H H bond 425 196 Me 8-Br iPr 2,4-FPh H H bond 550197 Me 8-Br iPr 3,5-FPh H H bond 550 198 Me 8-Me₂N H 4-FPh H H bond 454199 Me 8-Me H 4-ClPh H H bond 441 200 Me 8-Me iPr 4-ClPh H H bond 467201 Me 8-Cl H 4-FPh H H bond 445 202 Me 8-EtS H 4-FPh H H bond 471 203Me 8-piperidyl H 4-FPh H H bond 494 204 Me 9-Cl H 4-FPh H H bond 445 205Me 9-Br H 4-FPh H H bond 490 206 Et 8-OMe H 2-thienyl-5Cl H H bond 478207 iPr 8-OMe H 2-thienyl-5Cl H H bond 492 208 iBu 8-OMe H 2-thienyl-5ClH H bond 506 209 Bn 8-OMe H 2-thienyl-5Cl H H bond 540 210 Me 8-H H4-FPh H H CH₂ 425 211 Me 8-H H 3-FPh H H CH₂ 425 212 Me 8-MeO H 4-FPh HH CH₂ 455 213 Me 8-MeO H 3-FPh H H CH₂ 455 214 Me 8-Br H 4-FPh H H CH₂504 215 Me 8-Br H 3-FPh H H CH₂ 504 216 Me 8-MeO H 2-thienyl-5Cl 2-F Hbond 481 217 Me 8-NMe₂ H 4-ClPh H H bond 470

All of the compounds listed below in Table 2 relate to compounds of theformula (IF): TABLE 2

Example R¹ R² R³ R⁴ R⁵ R⁶ Z MH⁺ 8 H H H 4-ClPh H H bond 399 48 Me H H4-ClPh H H bond 413 49 Me H H 2-ClPh H H bond 413 50 H H H 3-ClPh H Hbond 399 51 Me H H 3-ClPh H H bond 413 52 Me H H 3,4-diClPh H H bond 44753 Me H H 2,4-dIClPh H H bond 447 54 H H H 4-BrPh H H bond 444 55 Me H H4-BrPh H H bond 458 56 Me H H 4-FPh H H bond 397 57 H H H 3-MePh H Hbond 379 58 Me H H 3-MePh H H bond 393 59 H H H 4-CF₃Ph H H bond 433 60H H H 4-OCF₃Ph H H bond 449 61 Me H H 4-OCF₃Ph H H bond 463 62 H H H4-t-BuPh H H bond 421 63 Me H H 4-t-BuPh H H bond 435 64 H H H5-Cl-2-thienyl H H bond 405 65 Me H H 5-Cl-2-thienyl H H bond 419 66 H HH 2-naphthyl H H bond 415 67 Me H H 2-naphthyl H H bond 429 68 H H Me4-ClPh H H bond 413 69 Me H Me 4-ClPh H H bond 427 70 H H H 4-ClPh 3-MeH bond 413 71 Me H H 4-ClPh 3-Me H bond 427 72 H 6-MeO H 4-ClPh H H bond429 73 H 6-MeO H 4-ClPh 3-Me H bond 443 155 H 6-MeO H 3-ClPh H H bond429 156 H 6-MeO H 2,4-diClPh H H bond 464 157 H 6-MeO H 2-Me-4-ClPh H Hbond 443 158 H 6-MeO H 4-MeOPh H H bond 425 159 H 6-MeO H 4-CNPh H Hbond 420 160 H 6-MeO H PhO H H O 411 161 H 6-MeO H 4-ClPhO H H O 445 162H 6-MeO H 2-thienyt H H bond 401 163 H 6-MeO H 3-thienyl H H bond 401164 H 6-MeO H 3-furanyl H H bond 385 165 H 6-MeO H 4-pyridyl H H bond396 166 H H H 4-ClPh 3-F H bond 417

All of the compounds listed below in table 3 relate to compounds offormula (IE): TABLE 3

Example R¹ R² R³ R⁴ R⁵ R⁶ Z MH⁺ 9 H H H 4-ClPh H H bond 385 10 Me H H4-ClPh H H bond 399 167 H H H 4-ClPh 3-Me H bond 399 168 Me H H 4-ClPh3-Me H bond 413 169 H H H 4-ClPh 3-F H bond 403 170 Me H H 4-ClPh 3-F Hbond 417 171 H H H 4-ClPh 3-CF₃ H bond 453 172 H H H 4-ClPh 3-MeO H bond415 173 Me H H 4-ClPh 3-MeO H bond 429 174 Me H H 4-ClPh 3-CF₃ H bond467

1. A compound of formula (I)

wherein A and B represent the groups —(CH₂)_(m)- and—(CH₂)_(n)-respectively; R¹ represents hydrogen or C₁₋₆alkyl; R²represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC₁₋₆alkyl,trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆alkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl,—(CH₂)_(p)C₃₋₆cycloalkyloxy, —COC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl,—S—C₁₋₆alkyl, C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfonylC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸, —SO₂NR⁷R⁸, C₁₋₆alkylsulfonamido,C₁₋₆alkylsulfonamidoC₁₋₆alkyl, —(CH₂)_(p)NR⁷R⁸, C₁₋₆alkylamidoC₁₋₆alkyl,—(CH₂)_(p)NR⁷COR⁸, arylsulfonyl, arylsulfonyloxy, arylsulfonylC₁₋₆alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamidoC₁₋₆alkyl,arylcarboxamidoC₁₋₆alkyl, aroyl, aroylC₁₋₆alkyl, arylC₁₋₆alkanoyl,—SO₂NR⁷R⁸, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl, or a group CONR⁷R⁸ orSO₂NR⁷R⁸ wherein R⁷ and R⁸ together may be fused to form a 5- 7-memberedaromatic or non-aromatic heterocyclic ring optionally interrupted by anO or S atom; R³ represents hydrogen or C₁₋₆alkyl; Ar representsoptionally substituted phenyl or optionally substituted monocyclicheteroaryl group; R⁴ represents optionally substituted aryl oroptionally substituted heteroaryl; R⁷ and R⁸ each independentlyrepresent hydrogen, C₁₋₆alkyl or together form a 5- to 7-memberedheterocyclic ring; Z represents a bond, an oxygen atom or C₁₋₆alkyl: Yrepresents hydrogen or C₁₋₆alkyl; m and n independently represent aninteger selected from 1 and 2; p independently represents an integerselected from 0, 1, 2 and 3; q represents an integer from 1 to 3; rrepresents an integer from 1 to 4; or a pharmaceutically acceptable saltor solvate thereof.
 2. A compound of formula (I) which is4-(4-Chloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-N-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-N-(2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-3-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-3-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamidehydrochloride;4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-3-,methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide;4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide;4-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamide;4-(4-Chloro-phenyl)-N-(8-dimethylamino-3-methyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)-benzenesulfonamidehydrochloride and4-(4-fluorobenzyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-benzenesulfonamidehydrochloride.
 3. A pharmaceutical composition comprising a compound offormula (I) as claimed in claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier therefor.
 4. Acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as claimed in claim 1, for use in therapy.
 5. A compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof asclaimed in claim 1 for use in a condition which requires modulation of adopamine receptor.
 6. A compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof according to claim 5 wherein thecondition is selected from psychotic disorders, Parkinsons disease,substance abuse, dyskinetic disorders, depression, bipolar disorder,anxiety, cognitive impairment, eating disorders, obesity, sexualdysfunction, sleep disorders, emesis, movement disorders,obsessive-compulsive disorders, amnesia, aggression, autism, vertigo,dementia, circadian rhythm disorders and gastric motility disorders. 7.(canceled)
 8. (canceled)
 9. A method of treating a condition whichrequires modulation of a dopamine receptor, which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as claimed in claim
 1. 10. A method of treating a conditionaccording to claim 9 wherein the condition is selected from psychoticdisorders, Parkinsons disease, substance abuse, dyskinetic disorders,depression, bipolar disorder, anxiety, cognitive impairment, eatingdisorders, obesity, sexual dysfunction, sleep disorders, emesis,movement disorders, obsessive-compulsive disorders, amnesia, aggression,autism, vertigo, dementia, circadian rhythm disorders and gastricmotility disorders.